INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TEMODALâ (TEMODALâ)

Composition:

Active substance: temozolomide;

1 capsule contains 20 mg or 100 mg of temozolomide;

Excipients: anhydrous lactose, anhydrous colloidal silicon dioxide, sodium starch glycolate (type A), tartaric acid, stearic acid;

capsule shell for 20 mg: gelatin, titanium dioxide (E 171), sodium lauryl sulfate, yellow iron oxide (E 172);

capsule shell for 100 mg: gelatin, titanium dioxide (E 171), sodium lauryl sulfate, red iron oxide (E 172).

Pharmaceutical form. Capsules.

Main physicochemical properties: capsules with a cap and an opaque white body. The capsules contain a powder ranging from white to light pink, light beige-brown color. The capsules are printed in black ink: on the cap – TEMODAL; on the body – two lines indicating either 20 mg or 100 mg and the Schering-Plough logo. The cap color corresponds to the dosage: yellow for 20 mg, opaque pink for 100 mg.

Pharmacotherapeutic group.

Antineoplastic agents. Alkylating agents. ATC code L01A X03.

Pharmacological properties.

Pharmacodynamics.

Temozolomide is a triazene that undergoes rapid chemical conversion at physiological pH values to the active compound 3-methyl-(triazene-1-yl)imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is believed to be primarily due to alkylation of guanine at the O6 position, with additional alkylation occurring at the N7 position. The resulting cytotoxic lesions are thought to involve a mechanism of aberrant repair of the methyl adduct.

Pharmacokinetics.

Temozolomide undergoes spontaneous hydrolysis at physiological pH levels, primarily forming the active species 3-methyl-(triazene-1-yl)imidazole-4-carboxamide (MTIC). MTIC then spontaneously hydrolyzes to 5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and methylhydrazine, which is likely the active alkylating species. The cytotoxicity of MTIC is believed to be primarily due to DNA alkylation, mainly at the O6 and N7 positions of guanine. With respect to AUC, exposure to MTIC and AIC is approximately 2.4% and 23%, respectively. In vivo, the t1/2 of MTIC is similar to that of temozolomide – 1.8 hours.

Absorption. After oral administration in adult patients, temozolomide is rapidly absorbed, reaching peak concentrations within 20 minutes after dose administration (median time from 0.5 to 1.5 hours). Following oral administration of 14C-labeled temozolomide, the mean fecal excretion of 14C over 7 days after dosing was 0.8%, indicating complete absorption.

Distribution. Temozolomide exhibits weak protein binding (10–20%), so interactions with substances that are highly protein-bound are not expected.

Studies using positron emission tomography (PET) in humans, as well as preclinical data, indicate that temozolomide rapidly crosses the blood-brain barrier and enters cerebrospinal fluid (CSF). The presence of the drug in CSF was confirmed in one patient; CSF exposure, relative to the AUC of temozolomide, was approximately 30% of plasma exposure, consistent with data obtained from animal studies.

Elimination. The elimination half-life (t1/2) of temozolomide in plasma is approximately 1.8 hours. The primary route of 14C elimination is via the kidneys. After oral administration, approximately 5–10% of the dose is excreted unchanged in urine within 24 hours, with the remainder excreted as temozolomide acid, 5-aminoimidazole-4-carboxamide, or unidentified polar metabolites.

Plasma concentrations increase in a dose-dependent manner. Plasma clearance, volume of distribution, and elimination half-life are independent of dose.

Special patient groups. Pharmacokinetic analysis of temozolomide has shown that its clearance is independent of patient age, renal function, or nicotine dependence. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild or moderate hepatic impairment were similar to those in patients with normal liver function.

In children, plasma concentration (AUC) is higher than in adults. However, the maximum tolerated dose for both children and adults is the same and equals 1000 mg/m2 per treatment cycle.

Clinical characteristics.

Indications.

Treatment:

of adult patients with newly diagnosed multiforme glioblastoma, in combination with radiotherapy followed by monotherapy;
of children aged 3 years and older and adult patients with malignant glioma in the form of multiforme glioblastoma or anaplastic astrocytoma at recurrence or disease progression after standard therapy.

Contraindications.

Temodal® is contraindicated in patients with:

hypersensitivity to the active substance or to any of the excipients;
hypersensitivity to dacarbazine (DTIC);
severe myelosuppression.

Special precautions.

Capsules must not be opened. If a capsule is damaged, contact of its contents with skin or mucous membranes should be avoided. In case of accidental exposure of Temodal® to skin or mucous membranes, the affected area should be immediately and thoroughly washed with soap and water.

Patients should store capsules out of reach of children, preferably in a locked cabinet. Accidental ingestion may be fatal for a child.

Any unused medicine or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other types of interactions.

Interaction studies have been conducted only in adult patients.

In a single Phase I study, co-administration of Temodal® with ranitidine did not alter the extent of temozolomide absorption or exposure to its active metabolite, MTIC.

Administration of Temodal® with food resulted in a 33% reduction in Cmax and a 9% reduction in AUC (area under the curve). Since a change in Cmax cannot be excluded as being clinically significant, Temodal® should not be taken with food.

Based on pharmacokinetic data from Phase II studies, concomitant administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine H2-receptor antagonists, or phenobarbital does not affect the clearance of Temodal®. Concomitant administration of valproic acid caused a mild but statistically significant reduction in temozolomide clearance.

Studies investigating the effect of temozolomide on the metabolism or elimination of other drugs have not been conducted. However, since temozolomide is not metabolized in the liver and exhibits minimal protein binding, clinically significant effects on the pharmacokinetics of other medicinal products are unlikely.

Concomitant use of Temodal® with other agents that suppress bone marrow function may increase the risk of myelosuppression.

Special precautions for use.

Opportunistic infections and reactivation of infections. Opportunistic infections (such as Pneumocystis jirovecii-associated pneumonia) and reactivation of infections such as hepatitis B and cytomegalovirus have been observed during treatment with Temodal® (see section "Adverse reactions").

Herpes meningoencephalitis. Post-marketing cases of herpes meningoencephalitis (including fatal cases) have been reported in patients receiving Temodal® in combination with radiotherapy, including when administered concomitantly with steroids.

Pneumocystis jirovecii pneumonia. Patients receiving Temodal® in combination with radiotherapy according to the extended 42-day treatment schedule have been at particular risk of developing Pneumocystis jirovecii pneumonia. Therefore, prophylaxis against Pneumocystis jirovecii pneumonia should be administered to all patients receiving concomitant Temodal® and radiotherapy according to the 42-day schedule (up to a maximum of 49 days), regardless of lymphocyte count. If lymphopenia occurs, prophylaxis should be continued until lymphopenia resolves to grade ≤ 1.

The incidence of Pneumocystis jirovecii pneumonia may be higher when Temodal® is used according to prolonged treatment schedules. All patients receiving Temodal®, and particularly those taking corticosteroids, should be monitored regularly for development of Pneumocystis jirovecii pneumonia, regardless of treatment schedule. Fatal cases due to respiratory failure have been reported in patients receiving temozolomide, particularly in combination with dexamethasone or other corticosteroids.

Hepatitis B virus. Reactivation of hepatitis B virus has been reported, in some cases resulting in fatal outcomes. Patients with positive serological markers for hepatitis B (including those with active disease) should be evaluated by a liver disease specialist prior to initiating treatment. Patients should be monitored during treatment and appropriate decisions regarding antiviral therapy should be made.

Hepatotoxicity. Hepatic injury, including fatal hepatic failure, has been reported in patients receiving Temodal®. Baseline liver function tests should be performed prior to initiating treatment. The physician should assess the benefit-risk ratio before initiating Temodal® therapy, including the potential for fatal hepatic failure. Patients receiving the 42-day treatment cycle should have liver function tests repeated during the cycle. Liver function tests should be monitored in all patients after each treatment cycle. The physician should reassess the benefit-risk ratio in patients with significant abnormalities in liver function. Hepatotoxic effects may occur several weeks (or later) after the last dose of Temodal®.

Malignant neoplasms. Very rare cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have also been reported.

Antiemetic therapy. Nausea and vomiting are very common with Temodal®; therefore, antiemetic therapy may be administered before or after drug administration.

Adult patients with newly diagnosed glioblastoma multiforme. Prophylaxis against vomiting is recommended prior to the first dose in the combined treatment phase and is strongly recommended throughout the monotherapy phase.

Patients with recurrent or progressive malignant glioma. Antiemetic therapy may be necessary for patients who experienced severe vomiting (Grade III or IV) in previous treatment cycles.

Laboratory parameters. Myelosuppression, including prolonged pancytopenia, may occur in patients receiving Temodal® and may lead to aplastic anemia, sometimes with fatal outcome. Assessment of some cases was complicated by concomitant use of drugs for treatment of aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim.

Prior to initiating Temodal® therapy, the following laboratory parameters should be met: absolute neutrophil count ≥ 1.5 × 10⁹/L and platelet count ≥ 100 × 10⁹/L. A complete blood count should be performed on Day 22 (21 days after the first dose) or within 48 hours thereafter, and then weekly until the absolute neutrophil count exceeds 1.5 × 10⁹/L and platelet count exceeds 100 × 10⁹/L. If the absolute neutrophil count is < 1.0 × 10⁹/L or platelet count is < 50 × 10⁹/L during any cycle, the dose in the next cycle should be reduced by one level. Available dose levels are 100 mg/m², 150 mg/m², and 200 mg/m² per day. The lowest recommended dose is 100 mg/m² per day.

Children. There is no clinical experience with the use of Temodal® in children under 3 years of age. Experience in older children and adolescents is very limited.

Elderly patients. Elderly patients (over 70 years of age) have a higher risk of developing neutropenia and thrombocytopenia compared to younger patients. Therefore, Temodal® should be used with caution in elderly patients.

Female patients. Women of childbearing potential must use effective contraception to prevent pregnancy during treatment with Temodal® and for at least 6 months after completion of therapy.

Male patients. Temodal® may exert genotoxic effects. Men receiving temozolomide therapy are advised not to plan conception for at least 3 months after the last dose. Sperm cryopreservation should be considered prior to starting treatment due to the potential for irreversible infertility associated with Temodal® therapy.

Lactose. Since Temodal® contains lactose, it should not be administered to patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Sodium.

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. There are no data on the use of the drug in pregnant women. Preclinical studies in rats and rabbits administered a dose of 150 mg/m² showed evidence of teratogenic and/or fetal toxicity. Therefore, Temodal® should not be given to pregnant women. If treatment during pregnancy is necessary, the woman should be informed of the potential risk to the fetus. Women of childbearing potential should be advised to use effective contraception to prevent pregnancy during treatment with Temodal®.

Breastfeeding. It is unknown whether Temodal® is excreted in human milk; therefore, breastfeeding should be discontinued during treatment with Temodal®.

Women of childbearing potential. Women of childbearing potential must use effective contraception to prevent pregnancy during treatment with Temodal® and for at least 6 months after completion of therapy.

Male fertility. Temodal® may have genotoxic effects. Men receiving this medication should use effective contraception and are advised not to plan conception for at least 3 months after the last dose. Advice regarding sperm cryopreservation should be sought before starting treatment due to the potential for irreversible infertility caused by Temodal® therapy.

Ability to affect reaction speed when driving or operating machinery.

The ability to drive or operate machinery may be slightly impaired during treatment with Temodal® due to the possible occurrence of fatigue and somnolence.

Method of administration and dosage.

Temodal® should be prescribed only by a physician experienced in oncological therapy for brain tumors.

Concomitant antiemetic therapy may be administered.

Temodal® capsules should be taken on an empty stomach.

The capsule should be swallowed whole with a glass of water. Capsules must not be opened or chewed.

If vomiting occurs after taking the medication, a second dose should not be taken on the same day.

Adult patients with newly diagnosed glioblastoma multiforme.

Temodal® is administered in combination with focal radiotherapy (concomitant phase), followed by 6 cycles of monotherapy with temozolomide (monotherapy phase).

Concomitant phase

Temodal® is administered orally at a dose of 75 mg/m² daily for 42 days concurrently with focal radiotherapy (60 Gy in 30 fractions). Dose reduction is not recommended; decisions regarding treatment interruption or discontinuation of Temodal® should be made weekly based on hematological and non-hematological toxicity criteria. Administration of Temodal® at the specified dose may be extended from 42 days of combined therapy to 49 days if all of the following conditions are met:

Absolute neutrophil count ≥ 1.5 × 10⁹/L;
Platelet count ≥ 100 × 10⁹/L;
Common Toxicity Criteria (CTC): non-hematological toxicity ≤ Grade 1 (excluding alopecia, nausea, and vomiting).

A complete blood count should be performed weekly during treatment. Administration of Temodal® should be interrupted or permanently discontinued during the concomitant phase of treatment according to hematological and non-hematological toxicity criteria as specified in Table 1.

Table 1

Interruption or permanent discontinuation of Temodal® during concomitant therapy (Temodal® + radiotherapy)

Toxicity	Temporary interruption of Temodal® treatment	Discontinuation of Temodal® treatment
Neutrophil count	³ 0.5 and < 1.5 × 109/l	< 0.5 × 109/l
Platelet count	³ 10 and < 100 × 109/l	< 10 × 109/l
CTC non-hematological toxicity (excluding alopecia, nausea and vomiting)	CTC grade 2	CTC grade 3 or 4

a The combined treatment phase (Temodar® + focal radiotherapy) may be continued if all the following conditions are met: absolute neutrophil count ≥ 1.5 × 10⁹/L; platelet count ≥ 100 × 10⁹/L; EORTC: non-hematological toxicity ≤ Grade 1 (excluding alopecia, nausea, and vomiting).

Monotherapy phase.

Four weeks after completion of the combined treatment phase (Temodar® + radiotherapy), 6 cycles of monotherapy with Temodar® are administered. The dose during cycle 1 (monotherapy) is 150 mg/m² once daily for 5 consecutive days, followed by a 23-day treatment-free period. The dose of Temodar® in cycle 2 is increased to 200 mg/m²/day if non-hematological toxicity according to EORTC during cycle 1 was ≤ Grade 2 (excluding alopecia, nausea, and vomiting), absolute neutrophil count ≥ 1.5 × 10⁹/L, and platelet count ≥ 100 × 10⁹/L. If dose escalation did not occur in cycle 2, the dose should not be escalated in subsequent cycles. If the dose was escalated, the drug should be administered at a dose of 200 mg/m²/day on Days 1–5 of each subsequent cycle, unless toxicity develops. Dose reduction or discontinuation of Temodar® during adjuvant therapy should be performed according to Tables 2 and 3.

A complete blood count should be performed on Day 22 (21 days after the first dose). Dose reduction or discontinuation of Temodar® should be carried out in accordance with the recommendations provided in Table 3.

Table 2

Dose levels of Temodar® for monotherapy

Level of dose	Dose (mg/m2/day)	Note
-1	100	Reduction due to prior toxicity
0	150	Dose during cycle 1
1	200	Dose during cycles 2–6 in the absence of toxicity

Table 3

Reduction of dose or discontinuation of Temodal® during monotherapy

Toxicity	Reduce dose of Temodal® by 1 levela	Discontinue Temodal®
Absolute neutrophil count	< 1.0 × 109/l	see reference b
Platelet count	< 50 × 109/l	see reference b
NCI non-hematological toxicity (excluding alopecia, nausea and vomiting)	NCI grade 3	NCI grade 4

aThe recommended doses of Temodal® are shown in Table 2.

bTemodal® should be discontinued if dose level –1 (100 mg/m²) is still associated with unacceptable toxicity or if grade 3 non-hematological toxicity (excluding alopecia, nausea, and vomiting) recurs after dose reduction.

Recurrent or progressive malignant glioma in adults and children aged 3 years and older

The treatment cycle is 28 days. For patients who have not previously received chemotherapy, Temodal® is administered once daily at a dose of 200 mg/m² for 5 consecutive days, followed by a 23-day treatment-free period. For patients who have previously received chemotherapy, the initial dose is 150 mg/m² once daily for 5 days; in cycle 2, the dose may be increased to 200 mg/m² once daily for 5 days, provided there is no hematological toxicity.

Special patient populations

Patients with hepatic or renal impairment

The pharmacokinetics of temozolomide are comparable in patients with normal hepatic function and those with mild to moderate hepatic impairment. There are no data on the use of temozolomide in patients with severe hepatic impairment (Child–Pugh class C) or in patients with renal impairment. Based on the pharmacokinetic properties of temozolomide, dose adjustment is unlikely to be necessary in patients with severe hepatic impairment or any degree of renal impairment. However, temozolomide should be used with caution in these patients.

Elderly patients

Pharmacokinetic data from studies involving patients aged 19 to 78 years indicate that temozolomide clearance is not age-dependent. However, elderly patients (over 70 years of age) are at increased risk of developing neutropenia and thrombocytopenia.

Children

Temodal® is indicated in children aged 3 years and older only for the treatment of recurrent or progressive malignant glioma. Experience with the drug in this patient group is very limited. The safety and efficacy of temozolomide in children under 3 years of age have not been established. No data are available.

Overdose

Doses of 500, 750, 1000, and 1250 mg/m² (total dose over a 5-day cycle) have been clinically evaluated. Dose-dependent hematological toxicity occurred at all dose levels, but, as expected, was more pronounced at higher doses. One patient received an overdose of 10,000 mg (total dose in one cycle over 5 days), resulting in pancytopenia, pyrexia, multi-organ failure, and death. Cases of bone marrow suppression (with or without infection), sometimes severe and prolonged, leading to fatal outcomes, have been reported in patients who received recommended doses (150–200 mg/m²) for more than 5 days (up to 64 days).

In the event of overdose, hematological monitoring is recommended and supportive treatment should be administered as needed.

Adverse Reactions

Summary of Safety Profile

Clinical Trial Experience

In patients receiving treatment with Temodal® during clinical trials, the most commonly reported adverse reactions were nausea, vomiting, constipation, anorexia, headache, fatigue, seizures, and rash. Most hematological adverse reactions were reported with "frequent" incidence; the frequency of grade 3–4 laboratory abnormalities is presented after Table 4.

In patients with recurrent or progressive glioma, nausea (43%) and vomiting (36%) were generally grade 1 or 2 (0–5 episodes of vomiting within 24 hours) and resolved spontaneously or were easily controlled with standard antiemetic therapy. The incidence of severe nausea and vomiting was 4%.

The list of adverse reactions is provided in Table 4.

Adverse reactions reported during clinical trials and post-marketing use of Temodal® are listed in Table 4. These adverse reactions are classified by system organ class and frequency. Frequency is defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 4

Adverse Reactions in Patients Receiving Temodal® Therapy

Infections and infestations
Common	infection, herpes simplex, pharyngitis¹, oral candidiasis
Uncommon	opportunistic infections (including Pneumocystis carinii-induced pneumonia), sepsis^§, herpes meningoencephalitis^§, cytomegalovirus infection, cytomegalovirus reactivation, hepatitis B virus^§, herpes simplex, reactivation of infections, wound infection, gastroenteritis²
Malignant and benign neoplasms (incl. unspecified)
Uncommon	myelodysplastic syndrome (MDS), secondary malignant neoplasm including myeloid leukemia
Blood and lymphatic system disorders
Common	febrile neutropenia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, anemia
Uncommon	prolonged pancytopenia, aplastic anemia^§, pancytopenia, petechiae
Immune system disorders
Common	allergic reactions
Uncommon	anaphylaxis
Endocrine disorders
Common	Cushingoid³
Uncommon	non-sugar diabetes
Metabolism and nutrition disorders
Very common	anorexia
Common	hyperglycemia
Uncommon	hypokalemia, increased alkaline phosphatase levels
Psychiatric disorders
Common	agitation, amnesia, depression, restlessness, confusion, insomnia
Uncommon	behavioral disorders, emotional lability, hallucinations, apathy
Nervous system disorders
Very common	convulsions, hemiparesis, aphasia/dysphasia, headache
Common	ataxia, balance disorder, cognitive disorders, decreased concentration, decreased level of consciousness, dizziness, hypesthesia, memory impairment, neurological disorders, neuropathy⁴, paresthesia, somnolence, speech disorder, taste distortion, tremor
Uncommon	status epilepticus, hemiplegia, extrapyramidal disorders, parosmia, gait disturbance, hyperesthesia, sensory disorders, coordination disorder
Eye disorders
Common	hemianopia, blurred vision, visual disturbance⁵, visual field defect, diplopia, eye pain
Uncommon	reduced visual acuity, dry eyes
Ear and labyrinth disorders
Common	deafness⁶, vertigo, tinnitus, ear pain⁷
Uncommon	hearing impaired, hyperacusis, otitis media
Cardiac disorders
Uncommon	palpitations
Vascular disorders
Common	hemorrhage, pulmonary embolism, deep vein thrombosis, hypertension
Uncommon	intracerebral hemorrhage, blood flush, hot flushes
Respiratory, thoracic and mediastinal disorders
Common	pneumonia, dyspnea, sinusitis, bronchitis, cough, upper respiratory tract infection
Uncommon	respiratory failure^§, interstitial pneumonitis/pneumonitis, pulmonary fibrosis, nasal congestion
Gastrointestinal disorders
Very common	diarrhea, constipation, nausea, vomiting
Common	stomatitis, abdominal pain⁸, dyspepsia, dysphagia
Uncommon	abdominal distension, fecal incontinence, gastrointestinal disorders, hemorrhoids, dry mouth
Hepatobiliary disorders
Uncommon	hepatic failure^§, liver damage, hepatitis, cholestasis, hyperbilirubinemia
Skin and subcutaneous tissue disorders
Very common	rash, alopecia
Common	erythema, dry skin, pruritus
Uncommon	toxic epidermal necrolysis, Stevens-Johnson syndrome, angioneurotic edema, erythema multiforme, erythroderma, skin exfoliation, photosensitivity reactions, urticaria, exanthema, dermatitis, increased sweating, pigmentation disorders
Unknown	drug reaction with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders
Common	myopathy, muscle weakness, arthralgia, back pain, musculoskeletal pain, myalgia
Renal and urinary disorders
Common	frequency of urination, urinary incontinence
Uncommon	dysuria
Reproductive system and breast disorders
Uncommon	vaginal bleeding, menorrhagia, amenorrhea, vaginitis, breast pain, impotence
General disorders and administration site conditions
Very common	fatigue
Common	fever, influenza-like symptoms, asthenia, malaise, pain, edema, peripheral edema⁹
Uncommon	worsening of general condition, tremor, facial edema, tongue color change, thirst, dental disorders
Laboratory findings
Common	increased liver enzymes¹⁰, weight loss, weight gain
Uncommon	increased gamma-glutamyl transferase (GGT) levels
Injury, poisoning and procedural complications
Common	radiation injury¹¹

1 Including pharyngitis, nasopharyngitis, streptococcal pharyngitis.

2 Including gastroenteritis, viral gastroenteritis.

3 Including Cushingoid, Cushing's syndrome.

4 Including neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral motor neuropathy.

5 Including visual impairment, eye disorders.

6 Including deafness, bilateral deafness, sensorineural deafness, unilateral deafness.

7 Including ear pain, ear discomfort.

8 Including abdominal pain, lower abdominal pain, upper abdominal pain, abdominal discomfort.

9 Including peripheral edema, peripheral swelling.

10 Including increased liver function test results: increased alanine aminotransferase levels, increased aspartate aminotransferase, increased liver enzymes.

11 Including radiation injury, radiation skin injury.

§ Including cases with fatal outcomes.

First-diagnosed glioblastoma multiforme

Laboratory findings

Myelosuppression (neutropenia and thrombocytopenia), which is a manifestation of dose-dependent toxicity common to most cytotoxic agents including temozolomide, was observed. During the combined treatment phase and temozolomide monotherapy, grade III or IV neutropenia was observed in 8% of patients, and grade III or IV thrombocytopenia in 14% of patients.

Recurrent or progressive malignant glioma

Laboratory findings

Grade III or IV thrombocytopenia and neutropenia were observed in 19% and 17% of patients, respectively, treated for malignant glioma. This led to hospitalization and/or discontinuation of temozolomide in 8% and 4% of patients, respectively. Myelosuppression was predictable (typically within the first few cycles, with nadir between days 21 and 28) and rapidly improved, usually within 1–2 weeks. There were no signs of cumulative myelosuppression. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Gender

According to population pharmacokinetic analysis, during the first treatment cycle, the highest incidence of grade IV neutropenia (absolute neutrophil count < 0.5 × 10⁹/L) was observed in 12% of women and 5% of men; grade IV thrombocytopenia (< 20 × 10⁹/L) occurred in 9% of women and 3% of men. In data from 400 patients with recurrent glioma, grade IV neutropenia occurred during the first treatment cycle in 8% of women and 4% of men, and grade IV thrombocytopenia in 8% of women and 3% of men. In a study involving 288 patients with newly diagnosed glioblastoma multiforme, grade IV neutropenia during the first treatment cycle was observed in 3% of women and 0% of men, and grade IV thrombocytopenia in 1% of women and 0% of men.

Pediatric population

Oral administration of temozolomide was studied in children (aged 3–18 years) with recurrent brainstem glioma or recurrent high-grade astrocytoma using a regimen of once daily for 5 days every 28 days. Although data are limited, tolerability of the drug in children is expected to be similar to that in adults. The safety of temozolomide in children under 3 years of age has not been established.

Shelf life

3 years.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

1 capsule in a sachet; 5 (1 × 5) or 20 (1 × 20) sachets in a cardboard box.

Prescription category By prescription only.

Manufacturer

Organon Heist N.V., Belgium.

Merck Sharp & Dohme B.V., Netherlands.

Manufacturer's address and place of business

Industriepark 30, 2220 Heist-op-den-Berg, Belgium.

Waarderweg 39, 2031 BN Haarlem, Netherlands.